Many medical deficiencies and diseases result from the inability of cells to produce normal biologically active compounds. Many of these deficiencies can be remedied by implanting a source of the needed biologically active compounds and/or pharmaceutical agents into the individual having the deficiency. A well known disease that can be remedied by implanting biological material and/or a pharmacological agent is Type I diabetes mellitus, wherein the production of insulin by pancreatic Langerhans islet cells is substantially deficient, impaired, or nonexistent.+
Type I or insulin dependent diabetes mellitus (IDDM) is a major, expensive public health problem causing renal and vascular disease, heart disease, blindness, nerve damage, major disability, and premature death. One treatment approach is the transplantation of insulin producing pancreatic islet cells (9,000 to 12,000 islets/kg), which can return blood sugar levels to normal and free patients from the need to take exogenous insulin. If blood sugars, insulin, and C-peptide levels can be normalized at an early stage of the disease, the complications of diabetes can be avoided. Major barriers to the clinical application of islet cell transplantation have been the problems of graft rejection, the scarcity of human organs, and the expense of their procurement. The medications used to prevent rejection are costly, increase the risk of infection, and can, themselves, induce hyperglycemia, hyperlipidemia, hypertension, and renal dysfunction, although progress is being made towards less toxic drug regimens.
Injection of islet cells is appealing because it is less invasive than whole organ pancreatic grafts and entails a lower morbidity rate. Transplanted human islets (allografts) have been shown to survive in the liver after administration of immunosuppressive drugs, but reliable long term function has been difficult to achieve. Injection into the liver is usually accompanied by heparinization to avoid thrombosis, which can increase the risk of ocular complications. Furthermore, human islets are a scarce and expensive cell type. Therefore, many researchers have suggested using animal cells (xenografts), particularly porcine islets. Pigs are plentiful, although porcine islets are relatively difficult to isolate and are fragile.
Unfortunately, the immunologic barriers to the successful transplantation of xenografts are even more difficult to surmount than those for the transplantation of allografts. Humans have natural pre-formed antibodies that can react with a saccharide, Gal alpha 1,3Gal(Gal), expressed on the cells of lower mammals to trigger hyperacute rejection. In addition, the complement regulatory proteins (decay accelerating factor, membrane cofactor protein, CD59) that normally help to control damage included by complement activation cannot function because they are species specific.
In light of the above hypothesis that immunoisolation of living allogeneic or xenogeneic insulin-producing islet cells by semi-permeable membranes provides a means for correcting diabetes mellitus. In order to avoid hyperacute rejection, the recipient's antibodies should be prevented from “seeing” the foreign proteins and activating complement. The encapsulating material should also reliably safeguard the patient from infectious processes (e.g., bacteria) unwittingly transferred with the animal cells. Materials used for immunoisolation should allow insulin, glucose, oxygen, and carbon dioxide to pass freely. These molecules have diameters less than 35 Angstroms (3.5 nm). Studies suggest that pore diameters of 30 nm can exclude the immigration of immunoglobulins, complement, and cytokines (e.g., tumor necrosis factor) providing immunoisolation. Unless immune tolerance can be established, such membranes should also prevent the out-migration of xeno-antigens into the host where they can activate the indirect pathway resulting in T helper cell activation. Immune graft rejection by direct cytotoxicity appears to be a major cause for loss of transplanted cells since donor cell viability is better in immune-compromised (CD4+ T cell depleted) mice. In addition, CD4+ cells secrete interferon-[gamma] that attracts and activates macrophages and NK cells. Macrophages, in turn, recruit T-cell help and initiate rejection. B-cell humoral mediated immunity also plays a role in xenograft rejection. There is, however, ample evidence that the immune response is not the sole source of xenograft failure.
Researchers, working with ovarian cell xenografts microencapsulated in HEMA (hydroxyethyl methacrylate-methyl methacrylate), found that cells began to lose function before the antibody response occurred. Other causes of graft failure include an inflammatory response to the chemistry of the encapsulating material, nutrient deficiency, accumulation of waste products and free radicals within the encapsulating material, and inadequate oxygen delivery.
In view of the foregoing, there is a need in the art for improved methods and/or implantable devices for providing insulin to treat and/or cure diabetes.